Preparation of new gem-difluoro heterocyclic-fused 1,2,3-triazole derivatives

Tetrahedron Letters 60 (2019) 292–296

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Preparation of new gem-difluoro heterocyclic-fused 1,2,3-triazole derivatives Layal Hariss a, Zeinab Barakat a, Farès Farès a, Thierry Roisnel b, René Grée b,⇑, Ali Hachem a,⇑ a b

Laboratory for Medicinal Chemistry and Natural Products, Lebanese University, Faculty of Sciences (1) and PRASE-EDST, Hadath, Beirut, Lebanon Univ Rennes, CNRS ISCR (Institut des Sciences Chimiques de Rennes), UMR 6226, F-35000 Rennes, France

a r t i c l e

i n f o

Article history: Received 18 November 2018 Revised 11 December 2018 Accepted 14 December 2018 Available online 15 December 2018 Keywords: Fluorine Propargylic fluorides Triazoles Heterocycles 1,3 Dipolar cycloaddition

a b s t r a c t Starting from easily accessible gem-difluoropropargylic derivatives a cascade nucleophilic substitution by N–3, followed by an intramolecular 1,3 dipolar cycloaddition, afforded in fair to good yields new 1,2,3-triazoles fused to pyrrolidines or piperidines. These molecules, with a gem-difluoro group vicinal to the triazoles, are fluorinated analogues of bioactive heterocycles. In parallel, a few open chain analogues have been prepared in order to evaluate the possible role of the bicyclic core on the biological properties of such molecules. Ó 2018 Elsevier Ltd. All rights reserved.

Introduction Heterocyclic compounds occupy a unique place in the realm of organic and medicinal chemistry [1]. 1,2,3-Triazoles are heterocycles of special interest, and they have been explored widely in drug design with numerous applications in various areas such as antiepileptic [2], antidiabetic [3], antitubercular [4], anti-inflammatory [5], antifungal [6], antiviral [7], antibacterial [8] and anticancer [9]. Fused 1,2,3 triazoles of general structure I (Fig. 1) have been less studied, although few representative examples have been obtained with Z as a carbon unit [10]. Some others have been reported as well with nitrogen [11], sulfur [12], and oxygen links [13]. Interestingly, a series of fused 1,2,3-triazoles have been synthesized and evaluated against several tumour cell lines. The most potent derivative was the 4-methoxy-phenylsubstituted 1,3-oxazaheterocycle fused 1,2,3-triazole II, which demonstrated good cytotoxicities against A431 and K562 tumour cell lines [13]. On the other hand, the introduction of fluorine, or fluoroalkyl groups, into organic molecules has attracted a great deal of attention in medicinal and bioorganic chemistry [14], since it induces major changes in their physical, chemical, and biological properties [15]. The CF2 group in particular, appears useful since it is generally

⇑ Corresponding authors. E-mail addresses: [email protected] (R. Grée), [email protected] (A. Hachem). https://doi.org/10.1016/j.tetlet.2018.12.032 0040-4039/Ó 2018 Elsevier Ltd. All rights reserved.

considered as a bioisosteric analogue of a carbonyl group, as well as of an ethereal oxygen [15a]. Efficient methods have been reported for the synthesis of triazoles, based on the 1,3 dipolar cycloaddition of azides and more recently using the ‘‘click chemistry” [16]. However there are only a limited number of examples with gem-difluorinated groups attached directly to triazoles. For instance, fluorinated triazoles have been synthesized to study the effect of fluorine atom(s) in propargylic position on the reactivity in click chemistry [17]. Other series of triazoles were prepared by Wenwen et al. via click reactions [18]. Finally, Okusu et al. have described the difluoromethylation of terminal alkynes by fluoroform and reactions of corresponding difluoromethylalkynes with benzyl azide, in the presence of a ruthenium catalyst [19]. Based on the promising biological activity of type-II compounds, we designed a strategy to prepare some gem-difluoro analogues such as compounds 1 or 2. To the best of our knowledge, no fluorinated fused triazole of this type has been reported to date. The goal of this publication is to describe a simple and efficient preparation of these molecules starting from known and easily available propargylic intermediates 3 (Scheme 1) [20]. The key step will be an intramolecular 1,3 dipolar cycloaddition of azides derived from 3. Furthermore, starting from the diol 4, precursor of 3, we have also prepared some open chain analogues 5 and 6. Such derivatives will be useful for biological studies in order to examine the possible role of the bicyclic core of molecules 1 and 2. It should be noticed that a patent has also reported promising

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n

Table 1 Preparation of fused-triazoles 1.

O

R

Z

O N

N

N

I

N 1

N

OH

F F

N

O

F F

Ar

N

N

II anticancer properties

Z= CR R , O, S, NR n=1,2 1 2

n

OMe

N

n

N

1

Entry

Starting material

n

Ar

HeterocyclesYield (%)

1 2 3 4 5 6 7

3-a1 3-a2 3-b1 3-b2 3-b3 3-b4 3-b5

1 1 2 2 2 2 2

3,5-dimethoxy 4-methoxy 3,5-dimethoxy 4-methoxy 2,6-dichloro Phenyl 3-bromophenyl

1-a1 (67) 1-a2 (61) 1-b1 (81) 1-b2 (84) 1-b3 (87) 1-b4 (64) 1-b5 (42)

Ar N

N

2

Fig. 1. Representative fused 1,2,3-triazole derivatives I and II with our target molecules 1 and 2.

O

F

F

OH

F

F

Ar

Ar n

N

N N

n n=1,2

1

N

N N n=1,2

2

Scheme 2. Preparation of fused 1,2,3-triazoles 1.

F F n

OH 3

Ar

Br F F n

OH Ar

4

HO

O

O

F F

HO

O Ar

n

N

N

F

HO

N

and

F

O Ar

First, bromide intermediate 3-a1 (n = 1 and Ar = 3,5-dimethoxyphenyl) was reacted with NaN3 in a mixture of dioxane and water at 100 °C to furnish triazolo-pyrrolidine 1-a1 in 67% yield (Table 1, entry 1). Under these conditions, the substitution by N–3 is followed immediately by the intramolecular 1,3 dipolar cycloaddition to obtain the desired bicyclic derivative 1-a1. In the same way, the bromide 3-a2 (n = 1 with Ar = 4-methoxyphenyl) afforded the expected derivative 1-a2 in good yield (Table 1, entry 2). Next, the substrates 3-b1 to 3-b5 (n = 2 with various Ar groups) were also transformed into the target triazole-fused piperidines 1b1 to 1-b5 in fair to good yields (42–87%) (Table 1, entries 3 to 7). All these molecules have spectral and analytical data in agreement with their structures. Further, in the case of 1-a1, 1-b1, 1b3, and 1-b4, they were confirmed by X-Ray crystallographic analysis (Fig. 2).

n

N

N N

5

6

Scheme 1. Retrosynthetic approach toward our targets 1, 2, 5 and 6.

properties against Alzheimer disease with various triazoles, including derivatives with a gem-difluoro side chain [21].

1-a1

1-

1-b3

1-b4

Results and discussion Seven representative bromides 3 were obtained by treatment of corresponding difluoropropargylic intermediates 4 with CBr4, and PPh3 in dichloromethane [20b]. They include systems with a 3 carbon chain (a: n = 1) as well as a four carbon linker (b: n = 2). Further, various aryl groups (Ar) have been introduced in propargylic position (Table 1). These bromides were used to prepare the target molecules (Scheme 2 and Table 1).

Fig. 2. Structures of 1-a1, 1-b1, 1-b3, and 1-b4 by X-Ray crystallographic analysis.

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Then oxidation, by Jones reagent, of the benzylic alcohols 1 afforded the target ketones 2 in 77–85% yields (Scheme 3 and Table 2). Compounds 2 have also spectral and analytical data consistent with their structure and in the case of 2-a2 and 2-b3 it was confirmed by X-Ray analysis (Fig. 3). Importantly, the derivative 2-a2 is the gem-difluoro analogue of II and therefore it will be of direct interest for the biological studies [22]. Then, in order to increase the molecular diversity around this scaffold, we performed two Suzuki-Miyaura reactions, as representative examples of Pd-catalyzed coupling processes. Starting from 1-b5 they afforded compounds 7 and 8 in 70% and 84% yields, respectively (Scheme 4). Finally, it appeared to us of interest to prepare in parallel a few analogues of similar triazoles but having open chains on both side, instead of the fused bicyclic system.

Ar n

N

N N

1

O

F

F

OH

F

F

The cycloaddition of three representative internal alkynes 4, [20b] with benzyl azide was carried out in DMF at 120 °C. The reaction proceeded smoothly to give a mixture of regioisomers 9 and 10 (Scheme 5, Table 3). These derivatives were separated by silica gel chromatography. After oxidation of 9 and 10 by Jones reagent, the corresponding keto carboxylic acids 5 and 6 were obtained in good yields (Scheme 6, Table 4). The structures of compounds 5-b4 and 6-b4 were established on the basis of X-Ray crystallography (Fig. 4), and these data confirm unambiguously the regiochemistry of the previous intermolecular 1,3-dipolar cycloaddition.

Ar

Scheme 5. Synthesis of triazoles 9, 10.

Jones reagent Acetone, 0°C

n

N

N N

2

n=1,2

n=1,2

Scheme 3. Oxidation of bicyclic triazoles 1.

Table 2 Preparation of ketones 2. Entry

Starting material

n

Ar

Heterocycles Yield (%)

1 2 3 4

1-a2 1-b1 1-b3 1-b5

1 2 2 2

4-methoxy 3,5-dimethoxy 2,6-dichloro 3-bromophenyl

2-a2 (85) 2-b1 (82) 2-b3 (81) 2-b5(77)

Table 3 Preparation of compounds 9 and 10. Entry

Starting material

n

Ar

Heterocycles Yield (%)

Ratio 9:10

1 2 3

4-a1 4-a2 4-b4

1 1 2

3.5-dimethoxy 4-methoxy Phenyl

(9-a1 + 10-b1) 65% (9-a2 + 10-b2) 57% (9-b4 + 10b4)82%

62:38 68:32 65:35

2-a2

2-b3 Scheme 6. Synthesis of keto carboxylic acids 5 and 6.

Fig. 3. Structure of 2-a2 and 2-b3 by X-Ray crystallographic analysis.

Table 4 Oxidation of diols 9 and 10.

Scheme 4. Suzuki-Miyaura reactions starting from 1-b5.

Entry

Starting material

n

Ar

HeterocyclesYield (%)

1 2 3 4

9-a2 10-a2 9-b4 10-b4

1 1 2 2

4-methoxy 4-methoxy phenyl phenyl

5-a2 (76) 6-a2 (77) 5-b4 (75) 6-b4 (82)

L. Hariss et al. / Tetrahedron Letters 60 (2019) 292–296

5-b4

6-b4

Fig. 4. The crystal structure of 5-b4 and 6-b4.

Conclusion In summary, we have designed a short and efficient synthesis of gem-difluoro heterocycle-fused 1,2,3-triazoles. Biological properties of these molecules are under study and corresponding results will be reported in due course. On the other hand, extension of the use of gem-difluoropropargylic intermediates to the preparation of other heterocyclic derivatives is under active study in our groups. Acknowledgments This work was financially supported by the Research Grant Program at Lebanese University (Lebanon). We thank all members of the two teams (Beirut and Rennes) for fruitful discussion and kind help. We thank CRMPO (Rennes) for the mass spectral analysis. We thank European FEDER founds for acquisition of D8Venture X-ray diffractometer used for crystal structure determination. Appendix A. Supplementary data Supplementary data to this article can be found online at https://doi.org/10.1016/j.tetlet.2018.12.032. References [1] a) For recent books see: J.J. Li, Heterocyclic Chemistry in Drug Discovery, Wiley, 2013; b) Z. Casar, in Synthesis of Heterocycles in Contemporary Medicinal Chemistry, Springer, 2016; c) E.F.V. Scriven, C.A. Ramsden, Advances in Heterocyclic Chemistry, Elsevier, 2017. [2] S. Kothare, G. Kluger, R. Sachdeo, B. Williams, O. Olhaye, C. Perdomo, F. Bibbiani, Seizure 47 (2017) 25–33. [3] E. Bokor, T. Docsa, P. Gergely, L. Somsak, Bioorg. Med. Chem. 18 (2010) 1171– 1180. [4] (a) C. Gill, G. Jadhav, M. Shaikh, R. Kale, A. Ghawalkar, D. Nagargoje, M. Shiradkar, Bioorg. Med. Chem. Lett. 18 (2008) 6244–6247; (b) R.P. Tripathi, A.K. Yadav, A. Arya, S.S. Bisht, V. Chaturvedi, S.K. Sinha, Eur. J. Med. Chem. 45 (2010) 142–148. [5] S. Syed, M.M. Alam, N. Mulakayala, C. Mulakayala, G. Vanaja, A.M. Kalle, Pallu R. Reddanna, M. Alam, S, Eur. J. Med. Chem. 49 (2012) 324–333. [6] (a) N.G. Aher, V.S. Pore, N.N. Mishara, A. Kumar, P.K. Shuka, A. Sharma, M.K. Bhat, Bioorg. Med. Chem. Lett. 19 (2009) 759–763; (b) J.N. Sangshetti, R.R. Nagawade, D.B. Shinde, Bioorg. Med. Chem. Lett. 19 (2009) 3564–3567; J.N. Sangshetti, A.R. Chabukswar, D.B. Shinde, Bioorg. Med. Chem. Lett. 20 (2010) 742–745. [7] (a) L. Zhou, A. Adel, M. Korn, R. Burda, J. Balzarini, E. Clercq, E.R. Kern, P.F. Torrence, Antiviral Chem. Chemother. 16 (2005) 375–383; (b) A.Sh. El-Etrawy, A.A.-H. Abdel-Rahaman, Chem. Heterocycl. Compd. 46 (2010) 1105–1108. [8] (a) B.S. Holla, M. Mahalinga, M.S. Karthikeyan, B. Poojary, P.M. Akberali, N. Suchetha Kumari, S, Eur. J. Med. Chem. 40 (2005) 1173–1178; (b) K.D. Thomas, A.V. Adhikari, N.S. Shetty, Eur. J. Med. Chem. 45 (2010) 3803– 3810. [9] N. Jagerovic, O.C. Gomez-de La, A . Cristina, M.P. Goya-Laza, Z.A. Dordal, M.R. Cuberes-Altisent, EP 1921072, May 14, 2008.

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After extraction with ethyl acetate, the organic phases were washed with H2O, dried over Na2SO4 and concentrated in vacuo. After purification by chromatography on silica gel, compounds 1 were obtained. (4,4-difluoro-5,6-dihydro-4H-pyrrolo[1,2-e][1,2,3]triazol-3-yl)(4methoxyphenyl)methanol (1-a2). Yellow oil, yield 17 mg (61%) from 30 mg (0.09 mmol); Rf : 0.20 (petroleum ether / AcOEt: 5/5); 1H NMR (CDCl3, 500 MHz): d, ppm: 7.39-7.37 (m, 1H), 7.37-7.36 (m, 1H), 6.88-6.87 (m, 1H), 6.876.85 (m, 1H), 6.00 (br. s, 1H), 4.52-4.48 (m, 2H), 3.78 (s, 3H), 3.28-3.20 (m, 2H). 13 C NMR (CDCl3,125 MHz): d, ppm: 159.5, 145.7, 133.6, 132.9 (t, 2J = 36.8 Hz), 127.8 (2C), 118.4 (t, 1J = 244.9 Hz), 113.9 (2C), 69.1, 55.2, 44.0, 40.5 (t, 2J = 27.2 Hz). 19F NMR (CDCl3, 470 MHz): d, ppm: -87.46 (AB system, J = 258.2 Hz). HRMS (ESI): calcd. for C13H13F2N3O2Na: m/z [M+Na]+ 304.0868; found: 304.0872 (1 ppm); calcd. for C13H13F2N3O2K: m/z [M+K]+ 320.06074; found: 320.0607 (0 ppm). General procedure for the synthesis of ketones 2. To alcohols 1 (9.00 mmol) in acetone (15 mL) was added dropwise under magnetic stirring at 0°C, a concentrated (5.4 M) solution of Jones reagent until disappearance of the starting material (TLC analysis). After addition of isopropanol (5 equiv), the reaction mixture was filtered and the residues were washed with ether. The combined organic phases were dried over

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L. Hariss et al. / Tetrahedron Letters 60 (2019) 292–296 Na2SO4, filtered and concentrated in vacuo. After purification by flash chromatography on silica gel, compounds 2 were obtained. (4,4-difluoro-5, 6-dihydro-4H-pyrrolo[1,2-e][1,2,3]triazol-3-yl)(4-methoxyphenyl)methanone (2-a2). White crystals, yield 8 mg (85%) from 10 mg (0.03 mmol); Rf : 0.73 (petroleum ether / AcOEt: 3/67; Mp = 148-150 oC. 1H NMR (CDCl3, 500 MHz): d, ppm: 8.57-8.55 (m, 1H), 8.55-8.53 (m, 1H), 7.03-7.01 (m, 1H), 7.01-6.99

(m, 1H), 4.69-4.65 (m, 2H), 3.90 (s, 3H), 3.45-3.37 (m, 2H). 13C NMR (CDCl3,125 MHz): d, ppm: 182.2, 164.1, 142.0, 139.9 (t, 2J = 37.4 Hz), 133.2 (2C), 128.8, 118.0 (t, 1J = 247.3 Hz), 113.8 (2C), 55.5, 44.5, 40.7 (t, 2J = 27.2 Hz). 19F NMR (CDCl3, 470 MHz): d, ppm: -89.65 (t, J = 12.6 Hz). HRMS (ESI): calcd. for C13H11F2N3O2Na: m/z [M+Na]+ 302.07115; found: 302.0718 (2 ppm); calcd. for C13H11F2N3O2K: m/z [M+K]+ 318.04509; found: 318.0455 (1 ppm).